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Toxicity and antitumor activity of the vitamin D analogs PRI-1906 and PRI-1907 in combined treatment with cyclophosphamide in a mouse mammary cancer model

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Abstract

Purpose

Active and less toxic vitamin D analogs could be useful for clinical applications. In the present study, we evaluated the toxicity and antitumor effect of two new synthetic analogs of vitamin D, namely PRI-1906 [(24E)-24a-Homo-(1S)-1,25-dihydroxyergocalciferol] and its side-chain unsaturated homo analog PRI-1907.

Methods

The toxicity and calcemic activity, as well as antitumor effect of calcitriol analogs was investigated in vivo. The studies were performed in a mouse mammary 16/C cancer model. Since calcitriol and its analogs inhibited 16/C tumor growth only slightly, we applied them in the combined therapy with cyclophosphamide (CY). Moreover, cell cycle analysis and VDR and p27 expression were investigated.

Results

The LD50 values after five daily subcutaneous (s.c.) injections were 7.8, 10.0 and 2.4 μg/kg per day for calcitriol, PRI-1906 and PRI-1907, respectively. The serum calcium level increased to 40, 23 and 63% over the control for these compounds. We also compare the antitumor activity of the PRI-1906 with the calcitriol and previously studied PRI-2191 (1,24-dihydroxyvitamin D3, tacalcitol). Statistically significant inhibition of tumor growth by calcitriol up to the eighth day was observed in all schedules applied. PRI-1906 inhibited the tumor growth at doses 1 and 5 μg/kg per day, and PRI-2191 only at the dose 5 μg/kg per day.

Conclusion

Addition of vitamin D analogs increased the antitumor effect of CY. PRI-1906 exhibited toxicity higher than PRI-2191 but lower than calcitriol and antitumor activity similar to both PRI-2191 and calcitriol. This new analog seems to be a good candidate for the combined treatment of mammary cancer.

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References

  1. Opolski A, Wietrzyk J, Chrobak A, Marcinkowska E, Wojdat E, Kutner A, Radzikowski C (1999) Antiproliferative activity in vitro of side-chain analogues of calcitriol against various human normal and cancer cell lines. Anticancer Res 19:5217–5222

    PubMed  CAS  Google Scholar 

  2. Asou H, Koike M, Elstner E, Cambell M, Le J, Uskokovic MR, Kamada N, Koeffler HP (1998) 19-nor vitamin-D analogs: a new class of potent inhibitors of proliferation and inducers of differentiation of human myeloid leukemia cell lines. Blood 92:2441–2449

    PubMed  CAS  Google Scholar 

  3. Li J, Finch RA, Sartorelli AC (1999) Role of vitamin D3 receptor in the synergistic differentiation of WEHI-3B leukemia cells by vitamin D3 and retinoic acid. Exp Cell Res 249:279–290

    Article  PubMed  CAS  Google Scholar 

  4. Oikawa T, Yoshida Y, Shimamura M, Ashino-Fuse H, Iwaguchi T, Tominaga T (1991) Antitumor effect of 22-oxa-1 alpha,25-dihydroxyvitamin D3, a potent angiogenesis inhibitor, on rat mammary tumors induced by 7,12-dimethylbenz[a]anthracene. Anticancer Drugs 2:475–480

    Article  PubMed  CAS  Google Scholar 

  5. Majewski S, Marczak M, Szmurlo A, Jablonska S, Bollag W (1995) Retinoids, interferon alpha, 1,25-dihydroxyvitamin D3 and their combination inhibit angiogenesis induced by non-HPV-harboring tumor cell lines. RAR alpha mediates the antiangiogenic effect of retinoids. Cancer Lett 89:117–124

    PubMed  CAS  Google Scholar 

  6. Norman AW, Mizwicki MT, Okamura WH (2003) Ligand structure-function relationships in the vitamin D endocrine system from the perspective of drug development (including cancer treatment). Recent Results Cancer Res 164:55–82

    PubMed  CAS  Google Scholar 

  7. Reichel H, Koeffler HP, Norman AW (1989) The role of the vitamin D endocrine system in health and disease. N Engl J Med 320:980–991

    Article  PubMed  CAS  Google Scholar 

  8. Opolski A, Wietrzyk J, Siwinska A, Marcinkowska E, Chrobak A, Radzikowski C, Kutner A (2000) Biological activity in vitro of side-chain modified analogues of calcitriol. Curr Pharm Des 6:755–765

    Article  PubMed  CAS  Google Scholar 

  9. Marcinkowska E, Kutner A, Radzikowski C (1998) Cell differentiating and anti-proliferative activity of side-chain modified analogues of 1,25-dihydroxyvitamin D3. J Steroid Biochem Mol Biol 67:71–78

    Article  PubMed  CAS  Google Scholar 

  10. Ji Y, Kutner A, Verstuyf A, Verlinden L, Studzinski GP (2002) Derivatives of vitamins D2 and D3 activate three MAPK pathways and upregulate pRb expression in differentiating HL60 cells. Cell Cycle 1:410–415

    PubMed  CAS  Google Scholar 

  11. Marcinkowska E, Kutner A (2002) Side-chain modified vitamin D analogs require activation of both PI 3-K and erk1,2 signal transduction pathways to induce differentiation of human promyelocytic leukemia cells. Acta Biochim Pol 49:393–406

    PubMed  CAS  Google Scholar 

  12. Elias J, Marian B, Edling C, Lachmann B, Noe CR, Rolf SH, Schuster I (2003) Induction of apoptosis by vitamin D metabolites and analogs in a glioma cell line. Recent Results Cancer Res 164:319–332

    PubMed  CAS  Google Scholar 

  13. Shokravi MT, Marcus DM, Alroy J, Egan K, Saornil MA, Albert DM (1995) Vitamin D inhibits angiogenesis in transgenic murine retinoblastoma. Invest Ophthalmol Vis Sci 36:83–87

    PubMed  CAS  Google Scholar 

  14. Young MR, Ihm J, Lozano Y, Wright MA, Prechel MM (1995) Treating tumor-bearing mice with vitamin D3 diminishes tumor-induced myelopoiesis and associated immunosuppression, and reduces tumor metastasis and recurrence. Cancer Immunol Immunother 41:37–45

    PubMed  CAS  Google Scholar 

  15. Zinser GM, Tribble E, Valrance M, Urben CM, Knutson JC, Mazess RB, Strugnell SA, Welsh J (2005) 1,24(S)-dihydroxyvitamin D2, an endogenous vitamin D2 metabolite, inhibits growth of breast cancer cells and tumors. Anticancer Res 25:235–241

    PubMed  CAS  Google Scholar 

  16. Lamprecht SA, Lipkin M (2003) Chemoprevention of colon cancer by calcium, vitamin D and folate: molecular mechanisms. Nat Rev Cancer 3:601–614

    Article  PubMed  CAS  Google Scholar 

  17. Welsh J, Wietzke JA, Zinser GM, Byrne B, Smith K, Narvaez CJ (2003) Vitamin D3 receptor as a target for breast cancer prevention. J Nutr 133:2425S–2433S

    PubMed  CAS  Google Scholar 

  18. Mehta RG, Hussain EA, Mehta RR, Das Gupta TK (2003) Chemoprevention of mammary carcinogenesis by 1α-hydroxyvitamin D5, a synthetic analog of vitamin D. Mutat Res 523–524:253–264

    PubMed  Google Scholar 

  19. Krishnan AV, Peehl DM, Feldman D (2003) The role of vitamin D in prostate cancer. Recent Results Cancer Res 164:205–221

    PubMed  CAS  Google Scholar 

  20. Smith DC, Johnson CS, Freeman CC, Muindi J, Wilson JW, Trump DL (1999) A Phase I trial of calcitriol (1,25-dihydroxycholecalciferol) in patients with advanced malignancy. Clin Cancer Res 5:1339–1345

    PubMed  CAS  Google Scholar 

  21. Peehl DM, Krishnan AV, Feldman D (2003) Pathways mediating the growth-inhibitory actions of vitamin D in prostate cancer. J Nutr 133:2461S–2469S

    PubMed  CAS  Google Scholar 

  22. Dalhoff K, Dancey J, Astrup L, Skovsgaard T, Hamberg KJ, Lofts FJ, Rosmorduc O, Erlinger S, Bach HJ, Steward WP, Skov T, Burcharth F, Evans TR (2003) A phase II study of the vitamin D analogue Seocalcitol in patients with inoperable hepatocellular carcinoma. Br J Cancer 89:252–257

    Article  PubMed  CAS  Google Scholar 

  23. Muindi JR, Peng Y, Potter DM, Hershberger PA, Tauch JS, Capozzoli MJ, Egorin MJ, Johnson CS, Trump DL (2002) Pharmacokinetics of high-dose oral calcitriol: results from a phase 1 trial of calcitriol and paclitaxel. Clin Pharmacol Ther 72:648–659

    Article  PubMed  CAS  Google Scholar 

  24. Beer TM, Hough KM, Garzotto M, Lowe BA, Henner WD (2001) Weekly high-dose calcitriol and docetaxel in advanced prostate cancer. Semin Oncol 28:49–55

    Article  PubMed  CAS  Google Scholar 

  25. Lowe LC, Guy M, Mansi JL, Peckitt C, Bliss J, Wilson RG, Colston KW (2005) Plasma 25-hydroxy vitamin D concentrations, vitamin D receptor genotype and breast cancer risk in a UK Caucasian population. Eur J Cancer 41:1164–1169

    Article  PubMed  CAS  Google Scholar 

  26. Wietzke JA, Ward EC, Schneider J, Welsh J (2005) Regulation of the human vitamin D3 receptor promoter in breast cancer cells is mediated through Sp1 sites. Mol Cell Endocrinol 230:59–68

    Article  PubMed  CAS  Google Scholar 

  27. Cho YL, Christensen C, Saunders DE, Lawrence WD, Deppe G, Malviya VK, Malone JM (1991) Combined effects of 1,25-dihydroxyvitamin D3 and platinum drugs on the growth of MCF-7 cells. Cancer Res 51:2848–2853

    PubMed  CAS  Google Scholar 

  28. Ravid A, Rocker D, Machlenkin A, Rotem C, Hochman A, Kessler-Icekson G, Liberman UA, Koren R (1999) 1,25-Dihydroxyvitamin D3 enhances the susceptibility of breast cancer cells to doxorubicin-induced oxidative damage. Cancer Res 59:862–867

    PubMed  CAS  Google Scholar 

  29. Siwinska A, Opolski A, Chrobak A, Wietrzyk J, Wojdat E, Kutner A, Szelejewski W, Radzikowski C (2001) Potentiation of the antiproliferative effect in vitro of doxorubicin, cisplatin and genistein by new analogues of vitamin D. Anticancer Res 21:1925–1929

    PubMed  CAS  Google Scholar 

  30. Chrobak A, Radzikowski C, Opolski A (2005) Side-chain-modified analogs of calcitriol cause resistance of human HL-60 promyelocytic leukemia cells to drug-induced apoptosis. Steroids 70:19–27

    Article  PubMed  CAS  Google Scholar 

  31. Abe J, Nakano T, Nishii Y, Matsumoto T, Ogata E, Ikeda K (1991) A novel vitamin D3 analog, 22-oxa-1,25-dihydroxyvitamin D3, inhibits the growth of human breast cancer in vitro and in vivo without causing hypercalcemia. Endocrinology 129:832–837

    Article  PubMed  CAS  Google Scholar 

  32. Abe-Hashimoto J, Kikuchi T, Matsumoto T, Nishii Y, Ogata E, Ikeda K (1993) Antitumor effect of 22-oxa-calcitriol, a noncalcemic analogue of calcitriol, in athymic mice implanted with human breast carcinoma and its synergism with tamoxifen. Cancer Res 53:2534–2537

    PubMed  CAS  Google Scholar 

  33. Beer TM, Lemmon D, Lowe BA, Henner WD (2003) High-dose weekly oral calcitriol in patients with a rising PSA after prostatectomy or radiation for prostate carcinoma. Cancer 97:1217–1224

    Article  PubMed  CAS  Google Scholar 

  34. Hartenbower DL, Stanley TM, Coburn JW, Norman AW (1977) Serum and renal histologic changes in the rat following administration of toxic amounts of 1,25-dihydroxyvitamin D3. 587–589

  35. Bouillon R, Okamura WH, Norman AW (1995) Structure-function relationships in the vitamin D endocrine system. Endocr Rev 16:200–257

    Article  PubMed  CAS  Google Scholar 

  36. Wietrzyk J, Pelczynska M, Madej J, Dzimira S, Kusnierczyk H, Kutner A, Szelejewski W, Opolski A (2004) Toxicity and antineoplastic effect of (24R)-1,24-dihydroxyvitamin D3 (PRI-2191). Steroids 69:629–635

    Article  PubMed  CAS  Google Scholar 

  37. Chodynski M, Wietrzyk J, Marcinkowska E, Opolski A, Szelejewski W, Kutner A (2002) Synthesis and antiproliferative activity of side-chain unsaturated and homologated analogs of 1,25-dihydroxyvitamin D2. (24E)-(1S)-24-Dehydro-24a-homo-1,25-dihydroxyergocalciferol and congeners. Steroids 67:789–798

    Article  PubMed  CAS  Google Scholar 

  38. Pelczynska M, Wietrzyk J, Jaroszewicz I, Nevozhay D, Switalska M, Kutner A, Zabel M, Opolski A (2005) Correlation between VDR expression and antiproliferative activity of vitamin D3 compounds in combination with cytostatics. Anticancer Res 25:2235–2240

    PubMed  CAS  Google Scholar 

  39. Peters GJ, van der Wilt CL, van Moorsel CJ, Kroep JR, Bergman AM, Ackland SP (2000) Basis for effective combination cancer chemotherapy with antimetabolites. Pharmacol Ther 87:227–253

    Article  PubMed  CAS  Google Scholar 

  40. Rak J, Kusnierczyk H, Strzadala L, Klosiewicz S, Radzikowski C (1989) Transplantable mouse mammary adenocarcinoma 16/c as a model in experimental cancer therapy. III. Sensitivity to antitumor drugs. Arch Immunol Ther Exp (Warsz ) 37:389–397

    CAS  Google Scholar 

  41. Verlinden L, Verstuyf A, Van Camp M, Marcelis S, Sabbe K, Zhao XY, De Clercq P, Vandewalle M, Bouillon R (2000) Two novel 14-Epi-analogues of 1,25-dihydroxyvitamin D3 inhibit the growth of human breast cancer cells in vitro and in vivo. Cancer Res 60:2673–2679

    PubMed  CAS  Google Scholar 

  42. Kumagai T, O’Kelly J, Said JW, Koeffler HP (2003) Vitamin D2 analog 19-nor-1,25-dihydroxyvitamin D2: antitumor activity against leukemia, myeloma, and colon cancer cells. J Natl Cancer Inst 95:896–905

    Article  PubMed  CAS  Google Scholar 

  43. Posner GH, Crawford KR, Peleg S, Welsh JE, Romu S, Gewirtz DA, Gupta MS, Dolan P, Kensler TW (2001) A non-calcemic sulfone version of the vitamin D3 analogue seocalcitol (EB 1089): chemical synthesis, biological evaluation and potency enhancement of the anticancer drug adriamycin. Bioorg Med Chem 9:2365–2371

    Article  PubMed  CAS  Google Scholar 

  44. Zhou JY, Norman AW, Akashi M, Chen DL, Uskokovic MR, Aurrecoechea JM, Dauben WG, Okamura WH, Koeffler HP (1991) Development of a novel 1,25(OH)2-vitamin D3 analog with potent ability to induce HL-60 cell differentiation without modulating calcium metabolism. Blood 78:75–82

    PubMed  CAS  Google Scholar 

  45. Campbell MJ, Reddy GS, Koeffler HP (1997) Vitamin D3 analogs and their 24-oxo metabolites equally inhibit clonal proliferation of a variety of cancer cells but have differing molecular effects. J Cell Biochem 66:413–425

    Article  PubMed  CAS  Google Scholar 

  46. Sabet SJ, Darjatmoko SR, Lindstrom MJ, Albert DM (1999) Antineoplastic effect and toxicity of 1,25-dihydroxy-16-ene-23-yne-vitamin D3 in athymic mice with Y-79 human retinoblastoma tumors. Arch Ophthalmol 117:365–370

    PubMed  CAS  Google Scholar 

  47. Hershberger PA, Yu WD, Modzelewski RA, Rueger RM, Johnson CS, Trump DL (2001) Calcitriol (1,25-dihydroxycholecalciferol) enhances paclitaxel antitumor activity in vitro and in vivo and accelerates paclitaxel-induced apoptosis. Clin Cancer Res 7:1043–1051

    PubMed  CAS  Google Scholar 

  48. Moffatt KA, Johannes WU, Miller GJ (1999) 1α,25dihydroxyvitamin D3 and platinum drugs act synergistically to inhibit the growth of prostate cancer cell lines. Clin Cancer Res 5:695–703

    PubMed  CAS  Google Scholar 

  49. Mazurkiewicz M, Opolski A, Wietrzyk J, Radzikowski C, Kleinrok Z (1999) GABA level and GAD activity in human and mouse normal and neoplastic mammary gland. J Exp Clin Cancer Res 18:247–253

    PubMed  CAS  Google Scholar 

  50. Love-Schimenti CD, Gibson DF, Ratnam AV, Bikle DD (1996) Antiestrogen potentiation of antiproliferative effects of vitamin D3 analogues in breast cancer cells. Cancer Res 56:2789–2794

    PubMed  CAS  Google Scholar 

  51. Ozono K, Sone T, Pike JW (1991) The genomic mechanism of action of 1,25-dihydroxyvitamin D3. J Bone Miner Res 6:1021–1027

    Article  PubMed  CAS  Google Scholar 

  52. Liao J, Ozono K, Sone T, McDonnell DP, Pike JW (1990) Vitamin D receptor interaction with specific DNA requires a nuclear protein and 1,25-dihydroxyvitamin D3. Proc Natl Acad Sci USA 87:9751–9755

    Article  PubMed  CAS  Google Scholar 

  53. Saramaki A, Banwell CM, Campbell MJ, Carlberg C (2006) Regulation of the human p21waf1/cip1 gene promoter via multiple binding sites for p53 and the vitamin D3 receptor. Nucleic Acids Res 34:543–554

    Article  PubMed  CAS  Google Scholar 

  54. Cheng HT, Chen JY, Huang YC, Chang HC, Hung WC (2006) Functional role of VDR in the activation of p27Kip1 by the VDR/Sp1 complex. J Cell Biochem 98:1450–1456

    Article  PubMed  CAS  Google Scholar 

  55. Huang YC, Chen JY, Hung WC (2004) Vitamin D3 receptor/Sp1 complex is required for the induction of p27Kip1 expression by vitamin D3. Oncogene 23:4856–4861

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments:

This research was supported by KBN (Polish State Committee for Scientific Research) Grant No. PBZ-KBN-091/P05/2003. Dmitry Nevozhay is supported by joint fellowship from the Jozef Mianowski Fund and Foundation for Polish Science. We would like to thank Prof. Czeslaw Radzikowski (IIET, PAS, Wroclaw) for critically reviewing the manuscript.

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Authors and Affiliations

  1. Department of Experimental Oncology, Institute of Immunology and Experimental Therapy, 12 R. Weigla St., 53-114, Wroclaw, Poland

    Joanna Wietrzyk, Dmitry Nevozhay, Magdalena Milczarek & Beata Filip

  2. Kopvillem Institute of Medical Physics, 64 Kirov St., 690068, Vladivostok, Russia

    Dmitry Nevozhay

  3. Pharmaceutical Research Institute, 8 L. Rydygier St., 01-793, Warsaw, Poland

    Andrzej Kutner

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  1. Joanna Wietrzyk
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Correspondence to Joanna Wietrzyk.

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Wietrzyk, J., Nevozhay, D., Milczarek, M. et al. Toxicity and antitumor activity of the vitamin D analogs PRI-1906 and PRI-1907 in combined treatment with cyclophosphamide in a mouse mammary cancer model. Cancer Chemother Pharmacol 62, 787–797 (2008). https://doi.org/10.1007/s00280-007-0666-6

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  • DOI: https://doi.org/10.1007/s00280-007-0666-6

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